tbuckley/cabot-search huggingface dataset:
Abstract 328: LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry
Authors: Hyejung Kim, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung, Changsik Park
Journal: Cancer Research (2022)

Abstract LCB84 is a human Trop-2-targeting antibody drug conjugate (ADC) composed of monomethyl auristatin E (MMAE) as payload and the Hu2G10 (by Mediterranea Theranostic) humanized IgG1 antibody that selectively targets the ADAM10-activated Trop-2 protein selectively expressed in transformed cancer cells (1). LCB84 was prepared using ConjuAll࣪, a proprietary site-directed conjugation technology of LegoChem Biosciences, which incorporates a conjugation ‘handle’ joined by enzymatic prenylation to a specifically engineered recognition sequence (CaaX) on antibody light chains. This conjugation handle facilitates simple versatile chemical conjugation to the linker-payload. A proprietary plasma-stable cleavable linker that is recognized and cleaved by a cancer-associated lysosomal enzyme, β-glucuronidase, was used to enable efficient and traceless payload release in a cancer-specific manner. LCB84 has been evaluated for anti-tumor activity and showed superior anticancer efficacy in triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), gastric cancer and non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) models compared to the ADC competitors Trodelvy and DS-1062. The LCB84 treatments were well tolerated, with no changes in body weight compared to control animals, for all dosing groups. LCB84 has robust cross-reactivity against primate Trop-2, which allows rigorous toxicity studies in monkeys. Remarkably, preliminary toxicity studies using cynomolgus monkeys showed that LCB84 is well tolerated, with calculated therapeutic index (TI, MTD/MED) of ~30 for single dosing and ~40 for repeat dosing. In conclusion, LCB84 is highly effective against Trop-2-positive CDX models in mice at doses that are well tolerated in mice and in primate models. Use of this proprietary plasma-stable cancer-selective linker technology and the Hu2G10 anti-Trop-2 monoclonal antibody that targets cancer-activated Trop-2 has led to a greatly improved next generation ADC for the treatment of various Trop-2-positive solid cancers including TNBC, PDAC, NSCLC and gastric cancer. Citation Format: Hyejung Kim, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung, Changsik Park. LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 328.
Abstract 2129: Spatial charting of single cell transcriptomes in tissues
Authors: Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Alastair Thompson, Ken Chen, Savitri Krishnamurthy, Nicholas Navin
Journal: Cancer Research (2022)

Abstract Single cell RNA sequencing (scRNA-seq) methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics (ST) assays can profile spatial regions in tissue sections but do not have single cell genomic resolution. To address this issue, computational approaches (e.g., cell2location, RCTD) have been designed to deconvolute ST spots into proportions of different cell types. However, the spatial deconvolution method has the following limitations, 1) it can only infer cell type proportions of each spot and cannot reach higher granular "cell states" mapping; 2) it only predict categorical labels and cannot infer continuous cell information (e.g., lineage trajectories, gene signatures, continuous phenotypes) at a spatial resolution. Here, we developed a computational approach called CellTrek that combines these two datasets to achieve single cell spatial mapping. Using a machine learning-based metric learning approach, CellTrek learned a cell-spot graph and then transfer spatial coordinates to cells. The CellTrek toolkit also provides two downstream analysis modules, including SColoc for spatial colocalization analysis and SCoexp for spatial co-expression analysis. We benchmarked CellTrek using a simulation and two in situ datasets. We then applied CellTrek to reconstruct cellular spatial structures in existing datasets from normal mouse brain and kidney tissues. We also performed scRNA-seq and ST experiments on two ductal carcinoma in situ (DCIS) tissues and applied CellTrek to identify subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data shows that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization into cellular neighborhoods and tissue structures. This method provides a new paradigm that is distinct from ST deconvolution, enabling a more flexible and direct investigation of single cell data with spatial topography. Citation Format: Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Alastair Thompson, Ken Chen, Savitri Krishnamurthy, Nicholas Navin. Spatial charting of single cell transcriptomes in tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2129.
Abstract 1143: ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent <i>in vivo</i> efficacy in gastric cancer patient-derived xenografts
Authors: Peng Chen, Yun Liu, Min Deng, Linjie Tian, Kevin Lynch, Bo Shan, Jay Mei, Bing Hou
Journal: Cancer Research (2022)

Abstract Background: Antibody-drug conjugates (ADCs) have become promising antitumor agents in recent years. ADCs are comprised of a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells, cross-linked to small molecule payloads with cytotoxic activity. Human Claudin 18.2 (CLDN18.2) is overexpressed in a large proportion of gastric and pancreatic cancers, with restricted normal tissue expression. The monoclonal antibody targeting CLDN18.2 (IMAB362) has demonstrated promising clinical benefit in combination with chemotherapies for gastric cancer patients. However, the same antibody shows suboptimal efficacy in patients with low CLDN18.2 expression. Here we report the potent in vivo efficacy of ATG-022, a CLDN18.2 ADC, in multiple gastric cancer patient-derived xenograft (PDX) models, including those with low CLDN18.2 expression. Methods: The binding affinity of ATG-022 with CLDN18.2 was detected by SPR and FACs analysis. The in vitro 50% inhibition concentration (IC50) of ATG-022 was determined in CLDN18.2 positive cell lines using CellTiter-Glo luminescent cell viability assay. In vivo efficacy of ATG-022 was evaluated in a series of gastric cancer PDX models with different expression level of CLDN18.2 The expression level of CLDN18.2 was determined using IHC staining. ATG-022 was dosed twice at 1 mg/kg, 3 mg/kg or 10 mg/kg every two weeks. Results: ATG-022 binds to CLDN18.2 protein with sub-nM affinity. It induced potent in vitro cytotoxicity in CHOK1 cells overexpressing CLDN18.2, with an IC50 of 5-7nM. Bystander killing by ATG-022 was observed. ATG-022 demonstrated potent in vivo antitumor efficacy in a gastric cancer PDX model with high CLDN18.2 expression. Intravenous dosing of 1 mg/kg, 3 mg/kg, and 10 mg/kg ATG-022 induced 35.41%, 71.56% tumor growth inhibition (%TGI) and tumor regression respectively. In a PDX model with low CLDN18.2 expression, 3 mg/kg ATG-022 or 10 mg/kg clinical benchmark CLDN18.2-ADC did not inhibit tumor growth, while 10 mg/kg ATG-022 induced tumor regression. Conclusions: ATG-022 demonstrated potent in vitro and in vivo antitumor effects, with in vivo efficacy observed in CLDN18.2-low expression PDX models, suggesting a promising therapeutic strategy for gastric cancer patients with a broad range of CLDN18.2 expression levels. Citation Format: Peng Chen, Yun Liu, Min Deng, Linjie Tian, Kevin Lynch, Bo Shan, Jay Mei, Bing Hou. ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1143.
Abstract 891: Therapeutic targeting of ovarian cancer stem cells using estrogen receptor beta agonist
Authors: Yi He, Salvador Alejo, Prabhakar P. Venkata, Jessica D. Johnson, Ilanna Loeffel, Julie Ann Martel, Uday P. Pratap, Suryavathi Viswanadhapalli, Rajeshwar R. Tekmal, Ratna K. Vadlamudi, Edward Kost, Gangadhara R. Sareddy
Journal: Cancer Research (2022)

Abstract Background: Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest that ovarian cancer stem cells (OCSCs) contribute to tumor relapse and chemotherapy resistance. Recent studies demonstrate that OCa cells express estrogen receptor beta (ERβ), which functions as a tumor suppressor. However, the status of ERβ expression in OCSCs and the therapeutic utility of ERβ agonist LY500307 for targeting OCSCs remain unknown. In this study, we tested the hypothesis that OCSCs express ERβ and that treatment with ERβ agonist reduces stemness and promotes apoptosis of OCSCs. Methods: We isolated subpopulations of OCSCs from SKOV3, A2780, and patient-derived ascites cells using ALDEFLUOR kit and examined the expression of ERβ in OCSCs using RT-qPCR. The effect of ERβ agonist LY500307 on OCSCs was examined utilizing cell viability, cell cycle, sphere formation, self-renewal, and apoptosis assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, and Western blot analysis. The efficacy of LY500307 on the tumor-initiating capacity of OCSCs was determined via in vivo limiting dilution assay studies using orthotopic intrabursal xenograft murine models. Results: RT-qPCR assay showed that ERβ, particularly ERβ isoform 1, is highly expressed in OCSCs compared to non-OCSCs. ERβ agonist LY500307 significantly reduced the viability of OCSCs compared to non-OCSCs. Treatment of OCSCs with LY500307 significantly reduced the sphere formation and self-renewal of OCSCs. Further, LY500307 treatment resulted in G2/M cell cycle arrest and promoted the apoptosis of OCSCs. Mechanistic studies using RNA-seq analysis demonstrated that ERβ agonist treatment resulted in the modulation of pathways related to cell cycle and apoptosis. Western blots and RT-qPCR assays confirmed the upregulation of genes involved in apoptosis and cell cycle arrest, such as FDXR and CDKN1A. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopically implanted OCa murine models. Conclusions: Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and may serve as a novel therapeutic agent in treating OCa Citation Format: Yi He, Salvador Alejo, Prabhakar P. Venkata, Jessica D. Johnson, Ilanna Loeffel, Julie Ann Martel, Uday P. Pratap, Suryavathi Viswanadhapalli, Rajeshwar R. Tekmal, Ratna K. Vadlamudi, Edward Kost, Gangadhara R. Sareddy. Therapeutic targeting of ovarian cancer stem cells using estrogen receptor beta agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 891.
Abstract 408: Development of a first-in-class notch transcription factor inhibitor CB-103 to overcome resistance to chemotherapy and targeted therapies
Authors: Michele Vigolo, Charlotte Urech, Sebastien Lamy, Samarpan Majumder, Lucio Miele, Rajwinder Lehal
Journal: Cancer Research (2022)

Abstract Human cancers possess striking ability to develop resistance to Standard of Care (SoC) designed to target specific hallmarks of cancer. This capability to develop resistance is in part due to cancer cell’s ability to activate alternative pathways and modulate tumor microenvironment to enhance cell survival, evade cell death and immunosurveillance. One such mechanism of developing resistance to SoC is the activation of the NOTCH pathway. NOTCH signaling is a developmental pathway which is known to be activated in several human cancers as a key oncogenic hit. In addition to its role as an oncogenic driver, activation of NOTCH is also known to induce resistance to several anti-cancer therapeutics in breast cancer and colorectal cancer. NOTCH signaling is known to cooperate with parallel oncogenic signals to impede activity of several drugs as a single agent. Previous agents targeting the NOTCH pathway upstream of the transcription complex were halted early in clinical development due to dose-limiting toxicities.Here we report activity of a novel first-in-class clinical stage CSL-NICD inhibitor in a panel of cell lines, xenograft and PDX models of human cancers in combination with several chemo and targeted therapies. Guided by in vitro and in vivo studies pre-clinical studies, CB-103 is currently being investigated in clinical trials as a single agent and in combination with SoC. Preliminary pre-clinical and clinical data shows desirable safety and efficacy profile of CB-103 enabling clinical development in combination with several therapeutic agents. Citation Format: Michele Vigolo, Charlotte Urech, Sebastien Lamy, Samarpan Majumder, Lucio Miele, Rajwinder Lehal. Development of a first-in-class notch transcription factor inhibitor CB-103 to overcome resistance to chemotherapy and targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 408.
Abstract 1036: Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer
Authors: Junghui Koo, Chang-Soo Seong, Bhakti Dwivedi, Carol Tucker-Burden, Adam I. Marcus, Melissa Gilbert-Ross
Journal: Cancer Research (2022)

Abstract Lung cancer is among the most commonly diagnosed cancers and the leading cause of cancer-related death globally, with approximately 85% of all lung cancers having non-small cell lung cancer (NSCLC). The protein kinase LKB1 is the 3rd most frequently mutated gene in lung adenocarcinoma, and serves as a master regulator of cell metabolism and growth. LKB1-inactivating mutations have a significant impact on NSCLC development. Although KRAS mutation is most frequently co-mutated with the tumor suppressor p53, the strongest cooperation was seen with homozygous inactivation of LKB1. Loss of LKB1 on a KRAS-mutant (KL) background leads to increased tumor burden, shortened survival time and increased metastasis compared to loss of TP53 (KP). Furthermore, inactivation or loss of LKB1 correlated with poor prognosis, where tumors are typically aggressive and chemoresistant. To discover therapeutic vulnerabilities for this aggressive genetic subtype of lung adenocarcinoma, we evaluated the contribution of multiple single- and double-genetic alterations (KRAS G12D (K), LKB1 knockdown (L), and p53 knockdown (P)) to 3D invasion phenotypes using immortalized human bronchial epithelial cells (HBEC3-KT) and conducted RNA transcriptome profiling of the invading HBEC3-KT 3D spheroids. We found that bone morphogenetic protein 6 (BMP-6) is upregulated in invasive KL spheroids only compared to K and KP, suggesting that the loss of both KL drives increased BMP6 expression. Consistent with this finding, the iron regulator hepcidin, which is regulated by BMP6 is also upregulated in KL spheroids. Both BMP-6 and hepcidin expression can be repressed by restoring exogenous LKB1 in KL spheroids suggesting that LKB1 loss is at least in part responsible for the overexpression of the BMP6/hepcidin pathway. In addition, inhibition of BMP-6 signaling via BMP type I receptor ALK2 using small molecule inhibitor LDN214117 suppressed of cell invasion in 3D culture and decreased tumor growth in a KL syngeneic mouse model. Collectively, our findings show that upregulation of hepcidin via BMP6 signaling and followed by iron sequestration in tumor cells is part of the metastatic invasion strategy of LKB1 inactivated NSCLC. Therefore, current clinical strategies targeting BMP6 signaling could improve outcomes for LKB1-mutant lung cancer patients. Citation Format: Junghui Koo, Chang-Soo Seong, Bhakti Dwivedi, Carol Tucker-Burden, Adam I. Marcus, Melissa Gilbert-Ross. Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1036.
Abstract 3129: TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse
Authors: Denay N. Stevenson, Ryne M. Holmberg, Samuel F. Gilbert, Mikella Robinson, Carrie D. House
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the deadliest gynecological cancer with over 13,000 deaths estimated in the United States this year. While there is an initial high response rate to cytotoxic chemotherapy, over 80% of advanced cases relapse within 24 months, presenting an urgent need to better understand the molecular mechanisms permitting relapse. Current research suggests that cancer recurrence can be attributed to a small subpopulation of cancer stem-like tumor-initiating cells (TICs) that possess the ability to both resist chemotherapy and initiate tumorigenesis. Our lab previously demonstrated an essential role for alternative NF-kB signaling in maintaining ovarian TICs, yet it is not fully understood how this pathway becomes activated in ovarian cancer. To begin to address this, we used an NF-kB reporter system to screen soluble factors known to be in the ovarian tumor microenvironment (TME) to identify the strongest inducers of NF-kB activation in ovarian cancer cells. We found that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a strong inducer of alternative NF-kB signaling. In vitro experiments demonstrate enhanced expression of stemness genes including SOX2, OCT4 and NANOG and increased spheroid formation ability after stimulation with TWEAK. Moreover, flow cytometry analysis of several TIC markers shows a significant enrichment of TICs when chemotherapy was combined with TWEAK, relative to chemotherapy alone. Stimulation of CD117+ cells led to higher expression of stemness genes relative to stimulation of CD117- cells, suggesting TWEAK activity may be specific to TICs and enhances their stem-like phenotype. In support of this, we found that CD117+ cells have higher expression of the TWEAK receptor FN14. We investigated the role of TWEAK in aiding relapse in vivo using an intraperitoneal xenograft mouse model and found that administration of a small molecule inhibitor of TWEAK-FN14 signaling as a maintenance treatment following chemotherapy significantly prolonged survival. These findings highlight a potential mechanism of TIC enrichment in response to chemotherapy that contributes to relapse. Citation Format: Denay N. Stevenson, Ryne M. Holmberg, Samuel F. Gilbert, Mikella Robinson, Carrie D. House. TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3129.
Abstract 2546: Targeting MerTK-mediated efferocytosis in the prostate cancer TME
Authors: Kayla V. Myers, Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, Kenneth J. Pienta
Journal: Cancer Research (2022)

Abstract The prostate cancer tumor microenvironment (TME) is comprised of many different components and cell types that influence tumor progression and patient outcome. Macrophages are highly abundant immune cells in the prostate cancer TME. Macrophage phenotypes can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages) and most macrophages in the prostate cancer TME are M2-like. Efferocytosis, the phagocytosis of apoptotic cells, is a pro-tumor function of M2-like macrophages. We have developed a flow cytometry assay to quantify efferocytosis of the prostate cancer cell line LNCaP. With both cell line-based THP-1 macrophages and human monocyte-derived macrophages (HMDMs), we observe that M2 macrophages efferocytose LNCaP cells more than M1 macrophages. Based on literature from other models and contexts, efferocytosis further supports the M2-like phenotype. Efferocytosis also prevents the apoptotic cell from progressing to secondary necrosis, which would attract an M1-like macrophage phenotype. Due these aspects, we hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages. Following efferocytosis of LNCaP cells by M2 HMDMs, we detect a decrease in the M1-like, anti-tumor marker CD80 and an increase in M2-like, pro-tumor markers CD206 and PDL1. Due to this role in modulating macrophage phenotype, we hypothesize targeting efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate, including M1-like macrophages. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. At both the protein and mRNA level, we detect higher MerTK expression in M2 than M1 THP-1 macrophages and HMDMs. Upon addition of apoptotic LNCaP cells, we observe an increase in phosphorylated MerTK (active form), suggesting the role of MerTK in prostate cancer cell efferocytosis. Currently, we are targeting MerTK to block prostate cancer cell efferocytosis in vitro and in vivo. We have generated a Mertk-/-, Hi-Myc mouse model on the FVB/N background. This prostate cancer GEMM will be used to assess the role of MerTK across different stages of prostate cancer progression. We will be comparing tumor size and immune infiltration between Mertk+/+ and Mertk-/- Hi-Myc mice aged to 2 months, 6 months and 12 months. We predict that the Mertk-/- mice will have smaller tumors and an overall anti-tumor immune infiltrate compared to Mertk+/+ mice in this model due to lack of efferocytosis. Citation Format: Kayla V. Myers, Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, Kenneth J. Pienta. Targeting MerTK-mediated efferocytosis in the prostate cancer TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2546.